Endothelin B receptor agonist, IRL-1620, provides long-term neuroprotection in cerebral ischemia in rats

We have earlier shown that stimulation of endothelin B receptors by IRL-1620 provides significant neuroprotection at 24h following cerebral ischemia. However, the effect of IRL-1620 is not known in the subacute phase of cerebral ischemia, where development of cerebral edema further contributes towards brain damage. This study was designed to determine the effect of IRL-1620 on neurological functions, infarct volume, oxidative stress, and endothelin receptors following permanent middle cerebral artery occlusion for 7 days. Rats received three intravenous injections of either vehicle or IRL-1620 [Suc-[Glu9,Ala11,15]-Endothelin-1(8-12)] at 2, 4, and 6h post occlusion. Treatment with IRL-1620 reduced infarct volume (54.06 ± 14.12 mm(3) vs. 177.06 ± 13.21 mm(3)), prevented cerebral edema and significantly improved all neurological and motor function parameters when compared to the vehicle-treated group. Vehicle-treated middle cerebral artery occluded rats demonstrated high levels of malondialdehyde and low levels of reduced glutathione and superoxide dismutase; these effects were reversed in IRL-1620 treated rats. No change in expression of endothelin A receptor was observed 7 days after induction of cerebral ischemia in vehicle or IRL-1620 treated rats. Rats receiving IRL-1620 demonstrated an upregulation of endothelin B receptor only in the infarcted hemisphere 7 days following occlusion. All effects of IRL-1620 were blocked by endothelin B receptor antagonist, BQ788. Results of the present study demonstrate that IRL-1620, administered on day 1, provides significant neuroprotection till 7 days after the induction of cerebral ischemia in rats. Selective endothelin B receptor activation may prove to be a novel therapeutic target in the treatment of cerebral ischemia.